Rett Syndrome (RTT) is an autism spectrum disorder (ASD) that results in mental retardation, motor dysfunction, seizures, and features of autism. RTT is caused by mutation of methyl-CpG binding protein 2 (MeCP2), a transcription factor. Little is known about the specific neurodevelopmental defects that underlie the complex clinical course of RTT. We have used the olfactory system, human olfactory nasal biopsies, and mouse models of MeCP2 mutation to demonstrate that MeCP2 is expressed with neuronal differentiation, and that MeCP2 mutation mimics the clinical course of RTT, causing distinct developmental and long term phases of compromised neuronal function. Our studies have revealed similarities in the neuronal defects found in RTT patients and mouse models of MeCP2 mutation, validating the olfactory system as a model for RTT. Acutely, Mep2 mutation disrupts neuronal terminal differentiation, axonal targeting, and synaptogenesis, while chronically, MeCP2 mutation affects synaptic organization and function. Our recent data indicate that MeCP2 mutation affects several signaling pathways that are important to synaptogenesis, and that sensory activity actually exacerbates this defect. Our overall hypothesis is that MeCP2 is critical for the establishment and maintenance of connectivity, which includes axonal targeting, synaptogenesis, and synaptic maintenance, including activity-induced synaptic refinement. Developmentally, MeCP2 mutation causes a transient delay of synaptogenesis, which, when overcome, reveals a long-term defects in synaptic structure and function. These defects are non-cell autonomous and are exacerbated by activity. As a consequence, and in an attempt to restore connectivity, neurotransmitter and neurotransmitter receptor expression is altered, resulting in further compromise. This complex course parallels the clinical course seen in RTT. The overall goal of the current proposal is to define the mechanisms that underlie the biological defects incurred by MeCP2 dysfunction to clarify the basis for neuronal compromise. We employ mouse models of MeCP2 mutations, in vivo and in vitro paradigms, and molecular and cell biological approaches. Aim 1 will investigate the non-cell autonomous mechanisms and signaling pathways that underlie the developmental and long term defects in connectivity in MeCP2 mutation. Aim 2 will study how MeCP2 mutation interferes with refinements in connectivity induced by sensory activity. Aim 3 will determine the effect of altering glutamatergic transmission on the acute and chronic neurobiological defects seen with MeCP2 mutation. Understanding the pathobiological mechanisms in RTT is essential to the implementation of therapeutic interventions, and moreover, may contribute to the understanding of the pathogenesis of other neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Rett Syndrome (RTT) is an autism spectrum disorder (ASD) that results in mental retardation, motor dysfunction, seizures, and features of autism. RTT is caused by mutation of MeCP2, a gene that affects brain gene expression, and a type of mutation that may underlie many ASDs. Little is known about the specific neurodevelopmental defects that underlie the complex clinical course of RTT. We use the olfactory system and mouse models of MeCP2 mutation to define the mechanisms that underlie the biological defects incurred by MeCP2 dysfunction to clarify the basis for neuronal compromise in ASDs.